AIDS 2016: Young Women Treated Very Early Stay HIV Negative and Preserve Immune Function

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A group of youngSouth African women who were diagnosed during very HIV early infection and immediately given antiretroviral therapy (ART) preserved their CD4 cell counts and the function of cells that HIV normally disrupts, according to a study presented at the 2016 Towards an HIV Cure Symposium, which preceded the 21st International AIDS Conference this week in Durban, South Africa. The majority of them never seroconverted, staying HIV-negative despite having evidence of low levels of HIV infection in their cells.

[Produced in collaboration with Aidsmap.com]

Researchers plan to follow these young women for 2 to 3 years, at which point a judgment will be made about offering them the option of undergoing an analytical treatment interruption (ATI) -- in other words, stopping their ART to see if they can remain undetectable without drugs.

The FRESH Study

Thumbi Ndung’u of the University of KwaZulu-Natal told the symposium of the latest data from the FRESH study. FRESH, among other things, is a study set up to show that it is possible to do HIV cure research among vulnerable young people in low-income settings, and look at options that may actually be practicable in those settings.

"Optimizing the effect of ART may be more feasible than other cure strategies in the African setting, at least in the short term," Ndung’u commented.

FRESH has recruited 300 young women aged 18-23 who are HIV-negative but at high risk of HIV infection, and its main aim is to evaluate the effect of giving ART during "hyperacute" infection -- the very earliest detectable stage, within no more than 3 weeks of infection and usually within 10-15 days, even before peak HIV viral load has been reached and well before HIV antibodies are generated.

In order to detect HIV infection this soon, the young women are given a test to detect HIV viral RNA no less than twice a week -- clearly a considerable commitment.

Despite coming into clinics for testing this often and being offered condoms and prevention advice, 42 of the young women have become infected with HIV, representing an annual incidence of 8.5%, or no different from background incidence. This incidence rate, if sustained, would mean that over 50% of these young women would have HIV within 8 years.

Of the 42 infected women, 28 received early ART, 24 of them within 15 days of infection. Of the 14 who chose not to take immediate ART, 11 had their infection detected within 15 days of exposure.

Among non-treated women, peak viral load was in the tens of millions of copies/mL at 10 days after being diagnosed, but had declined to a steady set-point averaging 30,000 copies/mL by 3-4 weeks after diagnosis. Their CD4 counts, averaging 800 cells/mm3 before infection, fell to 250 cells/mm3 during peak viremia, but then recovered -- though not completely -- to about 470 cells/mm3 by day 30.

The women treated immediately only developed a peak viral load of about 40,000 copies/mL and had viral loads below 50 copies/mL by day 30 after diagnosis. Their CD4 counts wavered slightly during peak viremia, but were at steady pre-infection levels by day 30.

Only 3 of 22 women treated with ART and with complete data available developed HIV antibodies and thus tested "HIV-positive." There was no relationship between peak viral load and whether women developed antibodies or not, but there was a slight relationship between missed clinic appointments and HIV seropositivity.

Some of the treated women developed no immune responses to HIV at all -- not just an absence of antibodies, but also a lack of CD8 cell responses. Of those that did, although they had fewer cells reactive to HIV, they developed a much stronger anti-HIV response. In contrast, in untreated women, their HIV-specific CD8 cells displayed a much more sluggish response to HIV (only 20% secreting the natural antiviral interferon-gamma) than to other viruses (60% to CMV, 100% to flu).

This finding is concordant with others presented at the symposium, suggesting that HIV does something specific to CD8 cells that leads to them becoming sluggish and unreactive. It probably does this by causing the cells to down-regulate or withdraw their receptors for other immune transmitters into themselves -- such as the CD127 receptor, the presence of which indicates cell longevity.

These findings may modify the "inflammation hypothesis" that HIV causes its damage by causing the immune system to burn out -- instead, it may specifically switch off parts of it. The HIV-specific CD8 cells in treated women had fully up-regulated CD127 molecules and secreted 10 times as much interferon-gamma.

Implications and Next Steps

While these findings are intriguing, the question is: what next for the treated women? Will their apparently very low levels of virus translate into an ability to contain it if they are taken off ART? This is a critical debate in cure research. Some scientists say that only treatment interruptions will tell us if early ART or other interventions lead to viral control off ART, while others want more animal model experiments and better surrogates for control before they consider treatment interruption for people. Ndung’u said that the current opinion of the trial ethics committee was that the women should be on ART for at least 2 to 3 years before considering treatment interruptions.

Related questions include how to educate the women who test HIV-negative that they still probably have the infection, and also whether PrEP (pre-exposure prophylaxis) should be part of what’s on offer to women with such high incidence. At a parallel meeting, the World Health Organization said that offering PrEP should be a priority for populations in which the rate of new HIV infections is 3% per year or greater. Ndung’u said that they were waiting for the South African government to issue its PrEP guidelines -- probably this autumn -- but would then likely offer it, even if it meant considerably altering incidence and therefore the trial’s power.

7/19/16

Reference

T Ndung’u. Addressing key gaps in cure research through identification and treatment of hyperacute HIV infection in a resource-limited setting. Towards an HIV Cure Symposium, 21st International AIDS Conference. Durban, July 16-17, 2016.